Is Proton Pump Inhibitor Therapy for Reflux Esophagitis Sufficient?: A Large Real-world Survey of Japanese Patients

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1 ORIGINAL ARTICLE Is Proton Pump Inhibitor Therapy for Reflux Esophagitis Sufficient?: A Large Real-world Survey of Japanese Patients Kazuhide Higuchi 1, Takashi Joh 2, Koji Nakada 3 and Ken Haruma 4 Abstract Objective Proton pump inhibitors (PPIs) are widely used as the mainstay of treatment for erosive reflux esophagitis, based on the excellent results obtained in clinical trials. However, the endoscopic remission rates in patients treated with PPIs in actual clinical settings have not been fully assessed. We conducted a nationwide survey to evaluate the effectiveness of PPIs based on endoscopic findings in real-world clinical settings. Methods This was a multicenter retrospective study conducted among 41 Japanese institutions. Endoscopic findings before and after PPI therapy were collected from the medical records of patients diagnosed with Los Angeles grade A-D reflux esophagitis who had been treated with a PPI for at least eight weeks before undergoing a second. The remission rates of erosive esophagitis, defined as the percentage of patients with grade N or M findings following PPI therapy, were calculated. Results Data for 541 patients were analyzed. At first, 45.5%, 30.3%, 15.9% and 8.3% of patients were diagnosed with grade A, B, C and D esophagitis, respectively. The mean duration of PPI therapy was 410 days, and the mean remission rate was 61.6%. The remission rate was significantly lower in the patients with more severe erosive esophagitis based on the LA grade before PPI therapy. Conclusion This study revealed that approximately 40% of the patients did not achieve remission of erosive esophagitis following PPI therapy for a mean of 1.1 years. This suggests the necessity of providing careful follow-up using periodic and appropriately selecting PPI therapy. Key words: esophagitis, proton pump inhibitors, atrophic gastritis, smoking (Intern Med 52: , 2013) () Introduction Gastroesophageal reflux disease (GERD), including erosive reflux esophagitis, has become common in daily clinical practice. In systematic reviews of epidemiologic studies, the prevalence of reflux esophagitis is % in Japan (1) and approximately 10-20% in Western countries (2). Recently, the prevalence of GERD in Japan has been increasing, most likely due to the aging of society, Westernization of the Japanese diet and decreases in Helicobacter pylori infection rates (3, 4). Proton pump inhibitors (PPIs), strong gastric acid suppressors, are used as the mainstay of treatment for reflux esophagitis (5-7). In a meta-analysis of prospective trials, 75-94% and 87% of patients achieved endoscopic remission after eight weeks of initial PPI treatment and one year of maintenance therapy, respectively (8). On the other hand, in the daily clinical setting, the endoscopic remission rate following PPI therapy remains obscure. Obtaining information on the real-life effectiveness of PPI therapy is necessary for the appropriate treatment and management of reflux esophagitis. We therefore conducted a nationwide retrospective survey Second Department of Internal Medicine, Osaka Medical College, Japan, Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan, Department of Surgery, The Jikei University School of Medicine, Japan and Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Japan Received for publication February 12, 2013; Accepted for publication March 5, 2013 Correspondence to Dr. Kazuhide Higuchi, higuchi@poh.osaka-med.ac.jp 1447

2 in Japan to evaluate the effectiveness of PPIs in patients with erosive reflux esophagitis based on endoscopic findings in real-world clinical settings. Study design Materials and Methods This was a retrospective survey conducted between October 2010 and March 2011 by gastrointestinal specialists of the GERD Society, a Japanese GERD study group, among 41 centers located throughout Japan. Most of the centers were relatively large general hospitals, including 22 university hospitals, seven public hospitals and six national hospitals. The medical records of patients who underwent upper gastrointestinal between August 2005 and July 2010 were reviewed, and up to 20 of the most recent consecutive patients at each center who met the selection criteria were identified for data collection. The collected data were checked for eligibility, then tabulated and analyzed. This survey was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research issued by the Ministry of Health, Labour and Welfare of Japan and was approved by the ethical committee of each center and Nishi Hospital, Higashi-Osaka, Japan. Patients All patients were diagnosed endoscopically with reflux esophagitis of grade A to D according to the LA classification and treated with PPIs for at least eight weeks before undergoing a second to reevaluate their modified LA classification (9) after PPI treatment. All patients were at least 20 years of age at the time of the first. Patients were excluded if they started PPI therapy more than one week before or more than four weeks after the first or if they terminated PPI therapy more than four weeks before the second. The other exclusion criteria were a history of comorbidity with malignancy, esophageal stricture, eosinophilic esophagitis, achalasia or malabsorption or a history of gastrointestinal resection or vagotomy. Data collection The patient s medical records were reviewed to collect data regarding patient characteristics, findings, PPI therapy, concomitant drugs, comorbidities and lifestyle. The patient characteristics comprised gender, age, height, body weight, and reflux symptoms at the time of the first. Height and body weight were used to calculate the body mass index (BMI). The reflux symptoms were determined based on reports of heartburn or acid reflux. Endoscopy findings before and after PPI therapy were used to assess the modified LA classification of the esophageal mucosa, which designates minimal mucosal lesions as grade M and is widely used by Japanese gastroenterologists (9). Concurrent findings during, such as hiatus hernia, gastritis or ulcers, were also recorded. The PPI therapy data comprised the dose and the start and termination dates. The doses of the PPIs used during therapy were categorized as standard, half or double doses. A standard dose was defined as 20 mg daily for omeprazole, 30 mg daily for lansoprazole and 10 mg daily for rabeprazole, based on the approved dose for initial treatment of reflux esophagitis in Japan. The duration of PPI therapy was calculated from the date of the start of PPI administration to the date of the second or the date of termination of PPI therapy, if earlier. Lifestyle factors included the regularity of daily habits, the smoking and alcohol consumption status and the consumption of caffeine-containing beverages or a high-fat diet at the time of the first. Statistics The primary variable of interest was the percentage of patients without erosive esophagitis, namely LA grade N or M, at time of the second. Associations between this percentage and other variables, including demographic data, the severity of esophagitis, the duration and dose of PPI therapy, comorbidities, concomitant drugs and lifestyle factors, were analyzed using a logistic regression analysis, the Kruskal-Wallis test and the chi-square test with significance set at p<0.05. All statistical analyses were conducted using the JMP software program (ver ; SAS Institute Inc., Cary, NC, USA). Patient backgrounds Results Data for 660 patients were collected from 41 centers. Of these patients, 119 were excluded owing to ineligibility or insufficient data (39 for PPI therapy lasting less than eight weeks, 60 for performed outside the period specified by the study protocol, four for lack of data and 16 for inconsistency of the PPI treatment period). The remaining 541 patients were included in the analysis. The patient characteristics are shown in Table 1. There were 337 men (62.3%), and the mean patient age was 63.9 years (range: years). At time of the first, 246 (45.5%), 164 (30.3%), 86 (15.9%) and 45 (8.3%) patients had LA grade A, B, C and D esophagitis, respectively (Table 1 and Figure a), and reflux symptoms, heartburn and acid reflux were observed in 339 patients (62.7%) (Table 1). The mean duration of PPI therapy was 410 days, and 366 patients (67.7%) received PPI therapy for more than six months before the second (Table 1). Among 539 patients for whom there were data on the PPI dose, 404 started their therapy with the standard dose and 110 started their therapy with the half dose (Table 2). Three hundred and fifty-five patients (65.6%) received standard-dose PPI therapy throughout the treatment period until the second, and 156 patients (28.8%) received half-dose therapy during the treatment period (Table 2). 1448

3 Table 1. Patient Characteristics Characteristic Male, n (%) 337 (62.3) Female, n (%) 204 (37.7) Mean age *, years (SD) 63.9 (13.2) LA grade before PPI therapy *, n (%) A 246 (45.5) B 164 (30.3) C 86 (15.9) D 45 (8.3) Reflux symptoms (heartburn or acid reflux) *, n (%) 198 (36.6) (62.7) Unknown 4 (0.7) Duration of PPI therapy, n (%) 8 w to 6 mo 175 (32.3) 6 12 mo 152 (28.1) 1 2 y 133 (24.6) >2 y 81 (15.0) Mean duration of PPI therapy, days (SD) (395.4) PPI: proton pump inhibitor * At time of first Until second Endoscopic remission of esophagitis at the second At the second, 61.6% (333/541) of the patients had LA grade N or M, hereafter referred to as the remission rate, and the remaining 38.4% (208/541) had grade A to D erosive esophagitis (Figure a). A comparison of the pretreatment severity of esophagitis showed that the remission rate was significantly lower in the patients with more severe esophagitis at the first (p<0.001, Kruskal- Wallis test) (Figure b). Among the patients with grade A at baseline, the remission rate was 70.7% (174/246). In contrast, among the patients with grade D at baseline, the remission rate was 42.2% (19/45) (Figure b). The remission rates did not differ significantly according to the dose of PPI (Table 2). Of the 355 patients who received standard-dose PPI therapy until the second, 220 (62.0%) achieved endoscopic remission (Figure c). The remission rates of the patients with and without experience of halfdose treatment were 63.5% and 61.1%, respectively (p= 0.608) (Table 2). Relationships between the patient characteristics and remission rates No significant differences were found in the endoscopic remission rates with respect to sex, age, BMI or reflux symptoms at time of the first (Table 3). Concomitant findings other than esophagitis were reported in 448 of the 541 patients (82.8%) at the first. Hiatus hernia and atrophic gastritis were found in approximately one-half of the patients: 49.7% (269/541) and 45.5% (246/541), respectively (Table 4). The remission rate did not differ significantly between the patients with and without hiatus hernia. However, the remission rate in the patients with open-type atrophic gastritis was significantly higher (72.2%) than that observed in the patients with closed-type (a) (b) (c) At first At second LA grade at first A (n=246) B (n=164) C (n=86) D (n=45) Standard dose (n=355) LA grade Ratio of patients (%) Ratio of patients (%) Ratio of patients (%) D C B A M N Figure. Percentage of patients with each LA grade. (a) The LA classification of the patients at the time of the first and second. (b) The LA classification of the patients at the second according to the LA grade at the first. (c) The LA classification of the patients treated with standard-dose proton pump inhibitors throughout the treatment period until the second. gastritis (58.0%, p=0.027) and those without atrophic gastritis (59.9%, p=0.021) (Table 4). The remission rate in the patients with superficial gastritis (63.1%) was lower than that observed in the patients without superficial gastritis (53.8%), although the difference was not significant (Table 4). Kyphosis was reported in 36 patients, and the remission rate in these patients (50.0%) was lower than that observed in the patients without kyphosis (64.4%), although the difference was not significant (Table 5). The remission rate did not differ significantly between the patients with and without other comorbidities reported at the time of the first (Table 5). The remission rates were not also significantly affected by the concomitant use of non-ppi GERD medications or other drugs (Table 5). 1449

4 Table 2. Proton Pump Inhibitor (PPI) Dose and Percentage of Patients with Endoscopic Remission PPI administration n (%) Remission rate * p Standard 404 (74.7) 61.6% PPI dose at start of therapy Double 25 (4.6) 52.0% Half 110 (20.3) 64.5% Unknown 2 (0.4) Standard 387 (71.5) 61.0% PPI dose at time of second Double 16 (3.0) 56.3% Half 136 (25.1) 64.7% Unknown 2 (0.4) No 383 (70.8) 61.1% Half-dose therapy during the Yes 156 (28.8) 63.5% treatment period Unknown 2 (0.4) * Percentage of patients without erosion of esophageal mucosa (LA grade N or M) at second Omeprazole 20 mg daily, lansoprazole 30 mg daily, or rabeprazole 10 mg daily Patients who did not receive half-dose therapy throughout the treatment period Patients who received half-dose therapy during the treatment period Table 3. Percentage of Patients with Endoscopic Remission by Patient Characteristics Characteristic n (%) Remission rate * p Sex Male 337 (62.3) 62.0% Female 204 (37.7) 60.8% Age (years) <40 32 (5.9) 65.6% (8.5) 71.7% (17.4) 52.1% (30.3) 61.6% (29.2) 63.9% (8.7) 59.6% Body mass index <20 51 (9.4) 66.7% (27.7) 60.0% (15.5) 65.5% (13.5) 67.1% Unknown 183 (33.8) Reflux symptoms (62.7) 62.8% 198 (36.6) 59.1% Unknown 4 (0.7) * Percentage of patients without erosion of esophageal mucosa (LA grade N or M) at second At time of first Wilcoxon s rank-sum test Information on lifestyle at baseline was collected from the medical records, if available. In 385 patients with data on smoking habits, the remission rate was significantly lower in the current smokers (54.3%) than in the nonsmokers (67.3%) (p=0.016) (Table 6). There were no significant differences in other lifestyle factors (Table 6). Discussion This is the first large-scale multicenter survey focused on the efficacy of PPIs in the treatment of erosive reflux esophagitis in real-world clinical situations in Japan. We found that esophageal erosion corresponding to LA grade A to D was present in approximately 40% of the patients who received PPI therapy for at least eight weeks before follow-up. In contrast, a meta-analysis of clinical trials reported that the healing rate after initial treatment is 75-94% after eight weeks of PPI therapy, while the endoscopic remission rate is 87% after maintenance therapy for one year (8). It should be noted that, in the present survey, the number of patients with erosive esophagitis at the second may have included patients with recurrent erosive esophagitis as well as those with unhealed disease. Nevertheless, the total remission rate in this survey (61.6%) is substantially lower than the healing rate after initial treatment and the endoscopic remission rate after maintenance therapy reported in prospective trials. There are several possible explanations for the relatively lower remission rate observed in this survey. When evaluating endoscopic findings after PPI therapy in real-world clini- 1450

5 Table 4. Percentage of Patients with Endoscopic Remission by Concomitant Findings on First Endoscopy Concomitant finding at first n (%) Remission rate * p Hiatus hernia 271 (50.1) 61.6% (49.7) 61.3% Atrophic gastritis 294 (54.3) 59.9% (45.5) 63.4% Closed type 112 (20.7) 58.0% Open type 108 (20.0) 72.2% Type unknown 26 (4.8) Superficial gastritis 447 (82.6) 63.1% + 93 (17.2) 53.8% Gastric ulcer 505 (93.3) 61.6% + 35 (6.5) 60.0% Duodenal ulcer 526 (97.2) 61.2% + 14 (2.6) 71.4% * Percentage of patients without erosion of esophageal mucosa (LA grade N or M) at second Versus patients without atrophic gastritis Closed type vs. open type Scar is excluded. cal situations, this survey included only patients who underwent a second after receiving PPI therapy. In some patients, the second may have been performed owing to the initial severe esophagitis or the presence of residual clinical symptoms based on the physician s judgment. Therefore, this survey may have been biased toward patients with a more severe pathology, although upper gastrointestinal is often conducted as part of routine health examinations in Japan (10). Indeed, this survey included a relatively large proportion of patients who were diagnosed with severe erosive esophagitis (24.2% had grade C or D esophagitis at the first ), whereas the proportion of such patients was % in previous epidemiologic studies conducted in Japan (3, 11, 12). Moreover, for each initial LA grade, the remission rates of the patients in this survey were substantially lower than the healing and remission rates reported in previous clinical trials (13-15). For example, in one randomized controlled trial, the healing rate of patients with grade A esophagitis was more than 95% after eight weeks of PPI treatment (15), whereas, in this survey, the remission rate in grade A patients was 70.7%. Interestingly, we found significant differences in remission rates in the analyses stratified according to the presence of atrophic gastritis and smoking habits at baseline. The patients with open-type atrophic gastritis at the first had a significantly higher remission rate than those with less progressed, closed-type atrophic gastritis and those without atrophic gastritis. Gastric mucosal atrophy is believed to decrease the risk of onset and recurrence of reflux esophagitis because it lowers gastric acid secretion (16-18). Our results imply that the presence of gastric atrophy is a prognostic factor with a positive influence on the remission of esophagitis following PPI therapy in clinical practice. However, further prospective studies are required to elucidate the relationship between the presence of gastric atrophy and the outcome of PPI therapy in patients with erosive reflux esophagitis. Numerous epidemiologic studies, including two recent Japanese cross-sectional studies, have reported an association between smoking and symptomatic GERD (2, 10, 19-21). Smoking cessation is recommended for GERD patients based on clinical experience, although clinical trial-based evidence to support the efficacy of smoking cessation for healing erosive esophagitis is lacking (7, 19). In the present survey, the remission rate was significantly lower in the current smokers than in the nonsmokers, which might strengthen the importance of physicians advice to stop smoking. However, this survey collected information on smoking habits at the time of the first, and any changes that may have occurred during PPI therapy are unknown. Therefore, the results presented here do not directly reflect the efficacy of smoking cessation in patients with erosive reflux esophagitis. Nevertheless, smoking cessation is useful for GERD patients because smoking is also a risk factor for Barrett s esophagus and esophageal adenocarcinoma (22, 23). 1451

6 Table 5. Percentage of Patients with Endoscopic Remission by Comorbidities and Use of Concomitant Drugs at Baseline Comorbidity / concomitant drugs n (%) Remission rate * p Kyphosis 345 (63.8) 64.4% + 36 (6.7) 50.0% Unknown 160 (29.6) Hypertension 356 (65.8) 60.7% (32.3) 63.4% Unknown 10 (1.8) Diabetes 461 (85.2) 60.7% + 70 (12.9) 67.1% Hyperlipidemia 440 (81.3) 60.2% + 91 (16.8) 68.1% Asthma 511 (94.5) 61.6% + 20 (3.7) 60.0% Depression 517 (95.6) 61.7% + 14 (2.6) 57.1% Sleep disorder 497 (91.9) 60.8% + 34 (6.3) 73.5% H 2 receptor antagonist 533 (98.5) 61.5% + 8 (1.5) 62.5% Prokinetic agent 494 (91.3) 61.1% + 47 (8.7) 66.0% Mucosal protectant 484 (89.5) 60.7% + 57 (10.5) 68.4% Calcium antagonist 431 (79.7) 60.8% (20.3) 64.5% NSAID 523 (96.7) 62.0% + 18 (3.3) 50.0% Low-dose aspirin 490 (90.6) 61.6% + 51 (9.4) 60.8% Steroid 523 (96.7) 61.6% + 18 (3.3) 61.1% Bisphosphonate 531 (98.2) 61.8% + 10 (1.8) 50.0% Antidepressant 506 (93.5) 60.7% (6.5) 74.3% Sleep-inducer 500 (92.4) 60.6% (7.6) 73.2% NSAID: non-steroidal anti-inflammatory drug * Percentage of patients without erosion of esophageal mucosa (LA grade N or M) at second In conclusion, this survey showed that, in real-world clinical situations, approximately 40% of patients still have erosive esophagitis after receiving PPI therapy for a mean of 1.1 years. The results may be biased because the survey included only patients who underwent a second based on their physician s judgment. However, the study implies that a considerable proportion of Japanese patients have erosive esophagitis even after long-term use of PPIs. We should bear in mind that, in daily clinical practice, reflux esophagitis is a refractory disease. Providing careful follow-up, including greater support and education to improve adherence to lifestyle advice and drug therapy, the use of periodic follow-up and the administration of an appropriate PPI, is required to improve the outcomes of treatment for reflux esophagitis. 1452

7 Table 6. Percentage of Patients with Endoscopic Remission by Lifestyle Factors at Baseline Lifestyle factor n (%) Remission rate * p Daily activities Quite regular 194 (35.9) 58.8% Somewhat irregular 55 (10.2) 70.9% Irregular 15 (2.8) 60.0% Unknown 277 (51.2) Current smoking 269 (49.7) 67.3% (21.4) 54.3% Unknown 156 (28.8) Alcohol consumption None 195 (36.0) 59.0% Once per week 49 (9.1) 61.2% 2 3 times per week 32 (5.9) 75.0% 4 times per week 99 (18.3) 67.7% Unknown 166 (30.7) Caffeinated beverages None 79 (14.6) 54.4% 1 2 cups per day 62 (11.5) 61.3% 3 cups per day 28 (5.2) 60.7% Unknown 372 (68.8) High-fat diet Hardly ever 53 (9.8) 58.5% Sometimes 91 (16.8) 57.1% Frequently 45 (8.3) 66.7% Unknown 352 (65.1) * Percentage of patients without erosion of esophageal mucosa (LA grade N or M) at second The authors state that they have no Conflict of Interest (COI). Acknowledgement This study was funded by the GERD Society. In addition to the authors, the following investigators participated in this study: T. Yamamoto, National Sanatorium Hoshizuka Keiaien; K. Murakami and S. Shiota, Oita University Faculty of Medicine; K. Sakurai and T. Murao, Graduate School of Medical Sciences, Kumamoto University; S. Inoue, National Hospital Organization Kochi National Hospital; F. Kinekawa and Y. Kita, Sanuki Municipal Hospital; Y. Shibazaki and Y. Bando, Ayagawacho National Health Insurance Sue Hospital; T. Toyokawa, National Hospital Organization Fukuyama Medical Center; T. Imaoka and Y. Moritou, Shimane Prefectural Central Hospital; N. Manabe, Kawasaki Medical School; T. Oshima, T. Tomita, Hyogo College of Medicine; E. Hayashi, Kinki Central Hospital; E. Masuda, National Hospital Organization Osaka Minami Medical Center; Y. Fujiwara and Y. Kohata, Osaka City University Graduate School of Medicine; H. Nebiki, Osaka City General Hospital; E. Umegaki and S. Tokioka, Osaka Medical College; N. Yoshida and T. Suzuki, Japanese Red Cross Kyoto Daiichi Hospital; M. Matsumoto and H. Moriyasu, Nara Prefectural Gojo Hospital; K. Kasugai, S. Izawa, Aichi Medical University School of Medicine; T. Kamiya, Nagoya City University Graduate School of Medical Sciences; T. Furuta and M. Sugimoto, Hamamatsu University School of Medicine; H. Mizuno, Toyama City Hospital; M. Inamori and Y. Sekino, Yokohama City University Hospital; Y. Watanabe and T. Hiraishi, St. Marianna University School of Medicine; N. Matsuhashi, NTT Medical Center Tokyo; J. Miwa and J. Tashiro, Toshiba General Hospital; A. Nagahara and M. Hojo, Juntendo University School of Medicine; H. Konishi and I. Ishikawa, Tokyo Women s Medical University; T. Matsuhisa, Tama-Nagayama University Hospital of Nippon Medical School; S. Takahashi and K. Nakamura, Kyorin University School of Medicine; D. Azuma, Azuma Clinic; M. Arai, Chiba University Hospital; M. Kusano and H. Hosaka, Gunma University Hospital; S. Kuribayashi, National Hospital Organization Numata National Hospital; K. Ikezawa, Tsukuba Memorial Hospital; Y. Mizokami and M. Hirose, University of Tsukuba; Y. Sasaki and H. Takeda, Faculty of Medicine, Yamagata University; M. Hongo and T. Shoji, Department of Comprehensive Medicine and the Department of Psychosomatic Medicine, Tohoku University Hospital; T. Koike and K. Nakagawa, Division of Gastroenterology, Tohoku University Graduate School of Medicine; M. Ohara, National Hospital Organization Hakodate National Hospital; M. Kato, Hokkaido University Hospital; and K. Harada and T. Nagashima, Harada Hospital. References 1. Kinoshita Y, Adachi K, Hongo M, Haruma K. Systematic review of the epidemiology of gastroesophageal reflux disease in Japan. J Gastroenterol 46: , Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 54: , Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. J Gastroenterol 44: , Kinoshita Y, Kawanami C, Kishi K, Nakata H, Seino Y, Chiba T. Helicobacter pylori independent chronological change in gastric acid secretion in the Japanese. Gut 41: , DeVault KR, Castell DO. Updated guidelines for the diagnosis 1453

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